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Acute Promyelocytic Leukemia: Mechanisms of PML‐RARα Action
Author(s) -
Reineke Erin Lynn,
Liu Heng,
Liu Yu,
Kao HungYing
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a966-b
Subject(s) - transactivation , transcription factor , acute promyelocytic leukemia , repressor , activator (genetics) , microbiology and biotechnology , biology , cancer research , gene , chemistry , retinoic acid , genetics
APL pathogenesis results from expression of a fusion protein resulting from a chromosomal translocation of various partners fused with the nuclear receptor RARα. Previous work shows that PML‐RARα homodimers are capable of binding co‐repressors more tightly than RXRα /RARα heterodimers, suggesting that PML‐RARα functions as a dominant negative of RARα and constitutively represses RARα target genes. However, in a promoter and cell‐type specific context, PML‐RARα can also activate expression of RARα target genes, implying that the currently proposed model is insufficient to explain the behavior of PML‐RARα. Our work focuses on how PML‐RARα contributes to oncongenic phenotypes through a study of its functional interactions with the co‐regulators. We have found that PML‐RARα acquires a hormone‐independent co‐activator association that is not seen with the RXRα /RARα heterodimer. This association applies to not only the p160 family members, but also the histone acetyltransferases, pCAF, p300 and CBP. Immunofluorescence microscopic studies indicate that ectopic overexpression of PML‐RARα results in redistribution of endogenous co‐activators. Functional assays indicate that PML‐RARα inhibits transactivation by GR and TAN‐1, which both require binding co‐activator complexes for activation of their target genes. Taken together, our data suggests that by binding and possibly sequestering co‐activators from other transcription factors, PML‐RARα may be able to effect normal cell regulation by de‐regulating a subset of genes whose activation requires co‐activators. American Cancer Society (RSG‐04‐052‐01‐GMC), NIH/NCI ROTG (T32 CA059366‐11)